The present invention is directed to a method for treating and preventing a migraine headache and other symptoms associated therewith using substituted phenylazacycloalkanes.
Migraine is a common, debilitating disorder that affects approximately 15% of the adult population. There are two major types of migraines, migraine without aura, which occurs in 85% of migraineurs, and migraine with aura. It has been apothesized that the activation of dopamine receptors may be involved in the pathophysiology of migraines since many of the symptoms associated with migraines can be attributed to the stimulation of dopamine receptors. That is, nausea, vomiting, gastrokinetic changes, hypotension, and other autonomic nervous system changes are migraine symptoms that are consistent with the activation of dopaminergic neurotransmission. Additional evidence of dopamine receptor hypersensitivity in migraineurs has been demonstrated by the induction of yawning, nausea, vomiting, hypotension and other symptoms of a migraine attack by dopaminergic agonists at doses that do not effect non-migraineurs.
In light of these findings, a variety of dopamine antagonists have been used in the acute treatment of migraine headaches. In a study, haloperidol, a potent D2 dopamine receptor antagonist, completely or substantially relieved headache in six of six patients within 25-65 minutes after administration. Fisher, J Emerg Med, 1995; 13: 119-122. Prochlorperazine is another D2 dopamine receptor antagonist that has demonstrated a high degree of efficacy in the acute treatment of a migraine. In a prospective, randomized, double-blind clinical trial of Prochlorperazine, 74% of the patients had complete relief and an additional 14% had partial relief within 60 minutes of administration. Jones et al, JMA 1989; 261: 1174-1176. Domperidone which, because of its poor blood-brain barrier penetration properties, is considered to be a peripheral D2 dopamine receptor antagonist. Domperidone has been shown to prevent the occurrence of a migraine if taken during the prodromal phase of the disorder. Amery et al, Headache 1983; 23: 37-38. Chlorpromazine has been reported to be highly effective in the treatment of migraine patients in an emergency department with moderate drowsiness as a common side affect. Lane et al, Headache 1985; 25: 302-304. Flunarizine is a compound which displays significant dopamine antagonist properties and a moderate degree of affinity for the D2 dopamine receptor. In studies, intravenous Flunarizine provided a high degree of relief in the acute treatment of migraine, with the highest response rate being observed in patients with xe2x80x9cclassical migrainexe2x80x9d. Soyaka et al, Headache 1989; 29: 21-27. Metoclopramide is a non-phenothiazine D2 dopamine receptor antagonist having a relatively low affinity for the D2 receptor and is commonly used in Europe in the treatment of migraine where it is usually an adjunct medication to improve the absorption of concurrent oral analgesics. Ellis et al, Ann Emerg Med 1993; 22: 191-195. Additionally, Metoclopramide has been shown to have a beneficial effect when given prophylactically to individuals with migraine. Practitioner 1974; 212: 887-890. Nearly all experienced clinicians have recommended the use of dopamine antagonists in combination with other agents in the treatment of migraine. Lance, Headache, Ann Neurol 1981; 10: 1-10. However, a common problem with these dopamine antagonists is that they have potential central nervous system side affects when given in higher doses.
Substituted phenylazacycloalkanes are disclosed in U.S. Pat. Nos. 5,462,947 and 5,594,024 to Svensson et al which possess selective dopamine receptor pharmacological properties and are useful in treating central nervous system disorders such as depression symptoms, geriatric disorders, schizophrenia, narcolepsy, MBD, obesity, disturbances of sexual function and rehabilitation of drug abusers. However, there is no disclosure in this reference that the substituted phenylazacycloalkanes can be used in the treatment of migraines.
The present invention is directed to a method of preventing the occurrence of migraine headaches and symptoms associated with migraine headaches in a person susceptible to the migraine headaches which comprises a step of administering to the person a pharmacologically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 
wherein n is 1 or 2; R1 and R2 are independently H, provided that both are not H, xe2x80x94OH, CN, CH2CN, 2- or 4-CF3, CH2CF3, CH2CHF2, CHxe2x95x90CF2, (CH2)2CF3, ethenyl, 2-propenyl, OSO2CH3, OSO2CF3, SSO2CF3, COR, COOR, CON(R)2, CONH2, SOxCH3, SOxCF3, O(CH2)xCF3, where x is 0-2, SO2N(R)2, CHxe2x95x90NOR, COCOOR, COCOON(R)2, C1-8 alkyls, C3-8 cycloalkyls, CH2OR, CH2(R)2, NRSO2CF3, NO2, halogen, phenyl in positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;
R3 is hydrogen, CF3, CH2CF3, C1-8 alkyl, C3-8 cycloalkyl, C4-9 cycloalkyl-methyl, C2-8 alkenyl, C2-8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, xe2x80x94(CH2)mxe2x80x94R5, where m is 1-8, CH2SCH3 or a C4-8 alkyl bonded to the N-atom and one of its adjacent carbon atoms to form a heterocyclic structure;
R4 and R are independently selected from hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-8 cycloalkyl, C4-9 cycloalkyl-methyl, C2-8 alkenyl, C2-8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, or xe2x80x94(CH2)mxe2x80x94R5, where m is 1-8;
R5 is phenyl, phenyl substituted with CN, CF3, CH2CF3, C1-8 alkyl, C3-8 cycloalkyl, C4-9 cycloalkyl-methyl, C2-8 alkenyl or C2-8 alkynyl, 2-thiophenyl, 3-thiophenyl, xe2x80x94NR6CONR6R7 or CONR6R7; and
R6 and R7 are independently hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C4-9 cycloalkyl-methyl, C2-8 alkenyl or C2-8 alkynyl.
Another embodiment of the present invention is directed to a method of treating a migraine headache and symptoms associated therewith in a person having a migraine headache attack comprising a step of administering to said person a pharmacologically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the compound of formula (I) is S-(xe2x88x92)-3-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine. The substituted phenylazacycloalkanes used in the present invention can be in the form of both racemic mixtures and pure enantiomers (R or S) but the preferred compounds have the S absolute configuration, according to the Cahn-Ingold-Prelog priority rules. Depending on the N-substituent, some of these S-enantiomers are dextrorotatory while others are levorotatory. The compounds can also be provided in the form of a pharmaceutically acceptable salt, such as a hydrochloride salt.
The present invention provides a method for preventing and treating the occurrence of migraine headaches and symptoms associated therewith through the use of substituted phenylazacycloalkane compounds without inducing the side affects associated with other dopamine antagonists. In the present invention, the substituted phenylazacycloalkanes can be administered concomittently with other medications used for the prevention and treatment of migraines.